Several lines of pharmacological and genetic evidence support the role of melanin concentrating hormone receptor-1 (hereafter “MCHR1”) as a modulator of food intake and body weight. Central administration of melanin concentrating hormone (MCH) increases food intake and body weight in both rats and mice. Chronic ICV infusion of MCH causes increased food intake and ultimately obesity in mice, while infusion of an MCH peptide antagonist blocks MCH-induced food intake and results in weight loss and decreased feeding in diet-induced obese mice.
The expression of both the MCH peptide and receptor are modulated by nutritional status. MCH mRNA is upregulated both in hyperphagic obese mice (ob/ob), and fasted animals. Targeted disruption of the gene for MCH peptide results in hypophagia and leanness. Disruption of the MCHR1 gene causes leanness, altered metabolism, and hyperlocomotion accompanied by mild hyperphagia. Conversely, over-expression of MCH peptide results in hyperphagia, obesity and diabetes. Small molecule MCHR1 antagonists have been shown to cause weight loss in rodent weight and feeding models after both oral and intraperitoneal administration; Takekawa, S. et al., Eur. J. Pharmacol., 438:129-135 (2002); Borowsky, B. et al., Nat. Med., 8:825-830 (2002); Kowalski, T. J. et al., Eur. J. Pharmacol., 497:41-47 (2004).
MCHR1 has also been reported to play a key role in the pathogenesis of acute experimental colitis and possibly human IBD (inflammatory bowel disease). It has been shown that immunoneutralization is an effective treatment for TNBS-induced colitis. Kokkotou, E. et al., “Melanin-concentrating hormone as a mediator of intestinal inflammation”, PNAS, 105(30):10613-10618 (2008).
In addition, MCH and MCHR1 have also been reported to play a role in the endocrine and behavioral responses to stress. Treatment of rats and mice with MCHR antagonists produces a robust anti-depressant and anti-anxiolytic effect (Gehlert, D. R. et al., JPET, 329(2):429-438 (2009)).
Non-peptide MCHR1 antagonists have been disclosed, but none of the MCHR1 publications disclosed pyrrolone or pyrrolidinone containing compounds as described in the present invention. In accordance with the present invention, there is provided a series of novel pyrrolone or pyrrolidinone MCHR1 antagonists.